Process for the manufacture of acyl-sulfonamides



Patented Mar. 4,1947

PROCESS FOR THE MANUFACTURE OF ACYL-SULFONAMIDES Henry Martin, Franz Hafiiger, and Otto Neracher, Basel, Switzerland, assignors to J. R. Geigy A. G., Basel, Switzerland, a Swiss firm No Drawing. Application May 1, 1944, Serial No. 533,659. In Switzerland May 21, 1943 6 Claims. (Cl. 260--397.7)

As known, aromatic acyl sulfonamides are produced by acylation of aromatic sulfonamides by means of acylating agents, like acid halides, acid anhydrides, etc., in the presence of condensation agents or acid binding agents. While the method with usual acylating agents gives satisfying yields, this is not the case, when functional derivatives of high molecular carboxylic acids are used. Moreover, valuable carboxylic acids are often accessible only with difficulty. A further disadvantage consists in that, for the purpose of acylation, valuable acid derivatives, like halides, anhydrides, etc, must be used which often are only obtainable with difiiculty. Moreover, the catalysts or acid binding agents, like aluminium chloride, dry pyridine and the like, which are indispensable for the condensation, are often chemically andqualitatively changed during the interactions so that they can no more or only with considerable costs be regenerated.

In contradistinction thereto we have now found that compounds of the general formula wherein R1 means an aliphatic, araliphatic, aromatic, cycloaliphatic or heterocyclic radical, R2 means an aromatic radical which is substituted by an amino group, and R3 represents a radical bound by means of a hetero atom, can easily be converted by means of hydrolysing agents into the corresponding acyl sulfonamides of the formula As starting materials for use in accordance with the invention sulfonylated amidines or imino ethers respectively may be employed, these prod-- ucts being accessible according to usual methods, for example by causing imino ethers to react with sulfonamides or according to U. S. Letters Pat-- ent No. 2,337,909, granted December 28-, 1943.

imino ethers with aromatic sulfohalides can in certain cases be obtained in an easier manner than the starting materials required for the methods known heretofore. Thus during the synthesis of carboxylic acids their nitril-es are often obtained as intermediate products. These lat ter compounds can be converted directly and in a smooth manner into the corresponding amidines and imino ethers and then be caused to react with aromatc sulfohalides. Thus it is not necessary to pass through the stages of the carboxylic acid and its halides, as was the case when working according to the known methods. Besides, the sulfohalides can be used as second reaction partner without the necessity of first converting the same into sulfonamides. Moreover, many nitriles can only be saponified with difiiculty, while they easily produce the corresponding amidines or imino ethers respectively.

The invention may now be illustrated, but not limited by the following examples, the parts being by weight.

Example 1 10 parts of N-( l-aminobenzene sulfone) -isovaleryl amidine (M. P. 118-120 C.)

, OH NH:

are heated for 2 hours to -100 C. with partsof 3.5% hydrochloric acid; after cooling the mixture is made alkaline with sodium carbonate, filtered and acidified by means of acetic acid. When recrystallised from dilute methyl alcohol, the 4-aminobenzene-N1-isovaleroyl sulfamide is obtained, this product melting at C. and having the following formula In the same manner for instance (a) N-( iaminobenzene su1fone)-butyryl amidine M. P. 70-72 C. or (b) N-(-aminobenzene sulfone) -isobutyryl amidine or (c) N-(l-aminobenzene su1fone)-[3:p-dimethyl acryl amidine M. P. 128-129 C. or (d) N-(l-aminobenzenesulfone) oc B p-trimethyl acryl amidine may also be hydrolysed to the corresponding acylated sulfonamides, namely: (a) 4-aminoben zene-Ni-butyroyl sulf amide M. P. 184-185 C. (d) 4-aminobenzene-N1- (cc p ,B-trimetyl acroyl) -sulfamide CH3 CH3 M. P. 181-182 C.

Example 2 10 parts of N-(4-aminobenzene su1fone)-4- methyl benzamidine M. P. 236 C. are heated for 3 hours to 9G-100 C. with 100 parts of 3.5% hydrochloric acid. Then the mixture is made alkaline in the cold by means of a sodium carbonate solution, filtered and acidified with acetic acid. When recrystallising from alcohol, the 4-aminobenZene-N1-(4- methylbenzoyD-sulfamide is obtained, the same melting at 173-179 C. and having the following formula In the same manner may be obtained from (a) N-( l-aminobenzene sulfone)- l-ethyl benzamidine or (b) N-(4-aminobenzene sulfone) -4'-propy1 benzamidine or (c) N-(4-aminobenzene sulfone)-4'-thioethyl ether benzamidine the corresponding acylated sulfonamides, namely: (a) 4=aminobenzene-N1-(4'-ethylbenzoyl) -su1famide M. P. 162-163 C. (b) 4-aminobenzene-N1-(4'- n-propyl benzoyl) -sulfamide 0113-0112-0112 OONH-Sz M. P. 162 C. (c) 4-aminobenzene-N1-(4'-thioethyl ether benzoyl) -sulfamide Example 3 10 parts of N-(4-aminobenzene sulfone)-3':4'- dimethyl benzamidine (M. P. 218-220 C.) of the formula are stirred for 12 hours at 90-100 C. in 100 parts of 3.5% hydrochloric acid. After cooling the mixture is made alkaline with sodium carbonate and worked up as indicated in Example 2. Thus the 4-aminobenzene-N1-(3:4'-dimethylbenzoyD-sulfamide of the melting point of 222 C. and of the formula is obtained in a good yield.

In an analogous manner for instance (a) N-(Flaminobenzene sulfone) -3'-n-propy1-4=methoxy CHaO- (b) N- l-aminobenzene methoxy-benzamidine (0) N-(4-aminobenzene sulfone)-A1-cyclopentenoyl amidine CC=N-SO2 NH'; l HPCH NH;

and (d) N-(4-aminobenzene sulfone)-A1-cyc1oheXenyl acetamidine may also be hydrolysed in order to give the corresponding acylated sulfonamides, i. e., (a) 4- aminobenzene-N1-(3' n propyl 4 methoxybenzoyl) -sulfamide CHZ-CH2-CH2 M. P. 202-203 C. (c) 4-aminobenzene-N1-(A1- cyclopentenoyl) -su1famide M. P. 202 Cfand (d) 4-amin0benzene-N1-(A1- cyclohexenylacetyl) -su1famide CHz-CHz cm-efl v M. P. 176-177 C.

Example 4 10 parts of N-(4-aminobenzene sulfone)-N'- diethyl-3':4-dimethyl benzamidine (M. P. 148- 150 C.) of the formula C2H5 are heated while stirring for 24 hours to 90-100 C. in 100 parts of 3.5% hydrochloric acid and worked up in the manner described in Example 2, Thus one obtains the 4-aminobenzene-N1-(3':4'- dimethylbenzoyl) -sulfamide melting at 222 C.

and having the formula.

The same final product. is also obtained by hydrolysing in accordance with the above example N (4 aminobenzene sulfone) N phenyl- 3:4-dimethy1 benzamidine (M. P. 198-200 C.) of the formula orig-z T=Nsoz -NH NH or the N '-dimethyl or N '-toly1 derivative.

Example 5 parts of N-(l-aminobenzene sulfone)-3:4'- dimethyl benzimino ethy1(or methyDether (M.- P. 328-329 C. under decomposition) of the formula Thus 4-aminobenzene -Ni(3'Af-di- .In an analogous manner (a) N l-aminoben zene sulfone) -4'-methyl benzimino ethyl ether.

and (b) N-(l-aminobenzene sulfone)-4"-ethy1 mercapto benzimino ethyl ether may be hydrolysed to give the corresponding acylated sulfonamides, namely: (a) 4-aminobenzene-N1- (4-methy1benz0y1) -sulfamide M. P. 1'78-179 C. and (b) 4-aminobenzene-N1- (F-ethyl mercapto benzoyD-sulfamide M. P. 185 C. Of course, also other imino alkyl ethers, such as the methyl, propyl, butyl ether, etc. may be used instead of the ethyl ether.

Example 6 1 part of N-(4-aminobenzene sulfone)-3':4- dimethyl hydrocinnamyl amidine of the formula is saponified with 10 parts of 3.5% hydrochloric acid, while stirring for 4- hours at l00 C., and worked up as indicated in Example 2. Thus one obtains the 4-amino-benzene-N1-(3:4'-dimethyl hydrocinnamoyl) -sulfamide of the melting point of 76'78 C. and of the formula In the same manner (a) N-(4-aminobenzene su1fone)-4methyl cinnamyl amidine (b) N-(4-aminobenzene sulfone) -4-methoxyfl-methyl cinnamyl amidine and (c) N-(-aminobenzene sulfone)-hydrooinnamyl amidine may be hydrolyzed to the corresponding acylated sulfonamides, namely; (a) 4-aminobenzene-N1- (4-methylcinnamoyl) -sulfamide M. P. 2G9-210 C. (b) 4-aminobenzene-N1-(4'- methoxy-p-methylcinnamoyl) -sulfamide 7 M. P. 182 184 C. and (c) 4-aminobenzene-N1- (hydrocinnamoyl) -sulfamide M. P. 160-161 C.

Example 7 parts of N-( l-aminobenzene sulfone)-anaphthamidine ll i ZI:S O rQNHa M. P. 182-184 C. are hydrolysed while stirring for 4 hours at 90100 C. by means of 3.5% hydrochloric acid and worked up according to Example 2. There is obtained the 4-aminobenzene- Nr-(u-naphthoyl) -su1famide of the melting point of-206-207 C.

In the same manner the following amidines may be hydrolysed: (a) N-(l-aminobenzene sulfone) -4 -methy1-1-naphthamidine NHz ' giving the 4 aminobenzene N1 (4-methyl-1- naphthoyl) -sulfamide of the formula M. P. 222 C. (b) N-(.l -aminobenzene sulfone)- p-naphthamidine giving the 4 aminobenzene-N1-( e-naphthoyl) sulfamide of the formula M. P. 205 C. (c) N-(l-aminobenzene sulfone) 1'-methoxy-2'-naphthamidine ll lc orgy 8 giving the 4 aminobenzene N 1-(l -methoxy-2t naphthoyl) -sulfamide of the formula 0 ONH-S o PUNK,

ACE: M. P. 230 C. (d) N-(4-aminobenzene su1fone)- 1-methy1-2'-idenylamidine giving the 4 aminobenzene N1 (1-methy1-2'- lndenoyl) -sulfamide of the formula M. P. 233 C. (under decomposition).

Example .8

10 parts of N-(4-aminobenzene su1fone)-afurylamidine l l L L$=Nso?- NH: NH-z Tr:

M. P. 165"-166 C. are transformed into the 4- aminobenzene N1 (a-furoyl) -sulfamide of the melting point of 188-189 C. and of'the formula by heating the starting product for hours with 100 parts of 3.5 per cent hydrochloric :acid and working up in the usual manner (according to Example 2) In an analogous manner there is obtained from N- (4-aminobenzene sulfone) -fi-pyridylamidine the 4-aminoloenzene N1-(nicotinoyl) -sulfamide of the formula M. P. 256-257 C.

What weclaim is: 1. A process for the manufacture of an N-acyl sulfonamide of the formula A process for the manufacture of an N- acyl sulfonamide of the formula wherein acyl represents a carboxylic acid radical of at least four carbon atoms, which comprises hydrolysing an N-sulfanilyl iminoether of a carboxylic acid of at least four carbon atoms by heating with an about 0.5-1 N mineral acid.

3. A process for the manufacture of an N-acyl sulfonamide of the general formula Acyl-NH-SOONHz 5. A process for the manufacture of N1-a,p,ctrimethylacroyl-sulfanilamide which comprises hydrolysing an a,B,fl-trimethylacry1ic acid N- sulfanilylamidine by heating with approximately 1 N mineral acid.

6. A process for the manufacture of N1-3,4-dimethylbenzoyl-sulfanilamide which comprises hydrolysing a 3,4-dimethylbenzoic acid N-sulfanilylamidine by heating with approximately 1 N mineral acid.

HENRY MARTIN. FRANZ HAFLIGER. OTTO NERACHER.

REFERENCES CITED The following references are of record in the file of this patent:

Kwartler et al., Jour. Am. Chem. Soc., vol. 65 (Mar. 1943), p 354-5.

Northey et al., Jour. Am. Chem Soc, vol. 64 (Dec. 1942), pp. 2763-5. 

